Our overall aim is to elucidate the structure of the mammalian circadian hierarchy. To accomplish this we need to know which organs and tissues contain independent circadian oscillators and how each is coupled to the others and to the environment to control phase and produce adaptive temporal organization. Our guiding hypothesis is that circadian oscillators in the suprachiasmatic nucleus of the hypothalamus (SCN) normally synchronize circadian oscillators in the brain and periphery using a variety of different signals. These include neural impulses, hormonal signals and, unexpectedly, behavioral signals generated by the SCN, modified by the environment, and acting on peripheral oscillators directly through the consequences of the behavior (e.g., feeding cycles entrain the circadian oscillators in the liver). Using transgenic rats in which the mouse Per1 promoter has been linked to a luciferase reporter, we have been able to measure circadian rhythms of light emission from a variety of cultured tissues including the SCN and peripheral tissues such as lung, liver and cornea. We will assess the degree to which the oscillators in peripheral tissues manifest canonical circadian properties such as temperature compensation. We will test the hypothesis that peripheral oscillators are maintained and regulated by a variety of different signals originating in the SCN by lesioning that structure and subsequently culturing peripheral tissues that oscillate when derived from intact animals. We will test the efficacy of several signals that putatively entrain peripheral oscillators (e.g., norepinephrine for pineal, insulin for liver, forced exercise for lung, melatonin and body temperature as systemic signals). Detailed knowledge of the coupling signals involved will eventually enable us to modify the phase of particular oscillators within the system for therapeutic purposes. This information is essential for the rational use of circadian approaches to the management of the performance deficits produced by shift work, insomnia and pathologies with circadian components such as seasonal affective disorder (SAD). Furthermore, it is basic to the design of treatments for many serious conditions (e.g., high blood pressure, cancer) in which responses to therapeutic agents are modulated both positively and negatively by the circadian system.